FOSAMPRENAVIR Drug Interactions: What You Need to Know

INTERACTIONS

• Coadministration of fosamprenavir with drugs that induce CYP3A4 may decrease amprenavir (active metabolite) concentrations leading to potential loss of virologic activity. ( 7 , 12.3 )
• Coadministration with drugs that inhibit CYP3A4 may increase amprenavir concentrations. ( 7 , 12.3 )
• Coadministration of fosamprenavir or fosamprenavir and ritonavir may result in clinically significant interactions with drugs metabolized by CYP3A4. ( 7 )
• Coadministration of fosamprenavir and ritonavir may result in clinically significant interactions with drugs metabolized by CYP2D6. ( 7 )

7.1 Cytochrome P450 Inhibitors and Inducers Amprenavir, the active metabolite of fosamprenavir, is an inhibitor of CYP3A4 metabolism and therefore should not be administered concurrently with medications with narrow therapeutic windows that are substrates of CYP3A4. Data also suggest that amprenavir induces CYP3A4. Amprenavir is metabolized by CYP3A4. Coadministration of fosamprenavir and drugs that induce CYP3A4, such as rifampin, may decrease amprenavir concentrations and reduce its therapeutic effect. Coadministration of fosamprenavir and drugs that inhibit CYP3A4 may increase amprenavir concentrations and increase the incidence of adverse effects. The potential for drug interactions with fosamprenavir changes when fosamprenavir is coadministered with the potent CYP3A4 inhibitor ritonavir. The magnitude of CYP3A4-mediated drug interactions (effect on amprenavir or effect on coadministered drug) may change when fosamprenavir is coadministered with ritonavir. Because ritonavir is a CYP2D6 inhibitor, clinically significant interactions with drugs metabolized by CYP2D6 are possible when coadministered with fosamprenavir plus ritonavir. Ritonavir also appears to induce CYP3A, CYP1A2, CYP2C9, CYP2C19, and CYP2B6, as well as other enzymes, including glucuronosyl transferase. There are other agents that may result in serious and/or life-threatening drug interactions <span class="opacity-50 text-xs">[see Contraindications (4) ]</span> .

7.2 Established and Other Potentially Significant Drug Interactions If fosamprenavir is used in combination with ritonavir, see full prescribing information for ritonavir for additional information on drug interactions <span class="opacity-50 text-xs">[see Contraindications (4) , Clinical Pharmacology (12.3) ]</span> .

Table

6 provides a listing of established or potentially clinically significant drug interactions. Information in the table applies to fosamprenavir with or without ritonavir, unless otherwise indicated.

Table

6. Established and Other Potentially Significant Drug Interactions Concomitant Drug Class: Drug Name Effect on Concentration of Amprenavir or Concomitant Drug Clinical Comment HCV/HIV-Antiviral Agents HCV protease inhibitor: Boceprevir Fosamprenavir: ↓ Amprenavir (predicted) ↔ or ↓ Boceprevir (predicted) Fosamprenavir/ ritonavir: ↓ Amprenavir (predicted) ↓ Boceprevir (predicted) Coadministration of fosamprenavir or fosamprenavir/ritonavir and boceprevir is not recommended. HCV protease inhibitor: Simeprevir Fosamprenavir: ↔ Amprenavir (predicted) ↑ or ↓ Simeprevir (predicted) Fosamprenavir/ ritonavir: ↔ Amprenavir (predicted) ↑ Simeprevir (predicted) Coadministration of fosamprenavir or fosamprenavir/ritonavir and simeprevir is not recommended. HCV protease inhibitor: Paritaprevir (coformulated with ritonavir and ombitasvir and coadministered with dasabuvir) Fosamprenavir: ↑ Amprenavir (predicted) ↑ or ↔ Paritaprevir (predicted) Fosamprenavir/ ritonavir: ↑ or ↔ Amprenavir (predicted) ↑ Paritaprevir (predicted) Appropriate doses of the combinations with respect to safety and efficacy have not been established.

Fosamprenavir

1,400 mg once daily may be considered when coadministered with paritaprevir/ritonavir/ombitasvir/dasabuvir. Coadministration of fosamprenavir/ritonavir and paritaprevir/ritonavir/ombitasvir/ dasabuvir is not recommended. Non-nucleoside reverse transcriptase inhibitor: Delavirdine See Clinical Pharmacology (12.3)

Tables

10 , 11 , 12 , or 13 for magnitude of interaction. Fosamprenavir: ↑ Amprenavir ↓ Delavirdine Fosamprenavir/ ritonavir: ↑ Amprenavir ↓ Delavirdine Coadministration is contraindicated as it may lead to loss of virologic response and possible resistance to delavirdine [see Contraindications (4) ] . Non-nucleoside reverse transcriptase inhibitor: Efavirenz Fosamprenavir: ↓ Amprenavir Appropriate doses of the combinations with respect to safety and efficacy have not been established. Fosamprenavir/ ritonavir: ↓ Amprenavir An additional 100 mg/day (300 mg total) of ritonavir is recommended when efavirenz is administered with fosamprenavir/ritonavir once daily. No change in the ritonavir dose is required when efavirenz is administered with fosamprenavir plus ritonavir twice daily. Non-nucleoside reverse transcriptase inhibitor: Nevirapine Fosamprenavir: ↓ Amprenavir ↑ Nevirapine Coadministration of nevirapine and fosamprenavir without ritonavir is not recommended. Fosamprenavir/ ritonavir: ↓ Amprenavir ↑ Nevirapine No dosage adjustment required when nevirapine is administered with fosamprenavir/ritonavir twice daily. The combination of nevirapine administered with fosamprenavir/ritonavir once-daily regimen has not been studied. HIV protease inhibitor: Atazanavir Fosamprenavir: Interaction has not been evaluated. Fosamprenavir/ ritonavir: ↓ Atazanavir ↔ Amprenavir Appropriate doses of the combinations with respect to safety and efficacy have not been established. HIV protease inhibitors: Indinavir , nelfinavir Fosamprenavir: ↑ Amprenavir Effect on indinavir and nelfinavir is not well established. Fosamprenavir/ ritonavir: Interaction has not been evaluated. Appropriate doses of the combinations with respect to safety and efficacy have not been established. HIV protease inhibitors: Lopinavir/ritonavir ↓ Amprenavir ↓ Lopinavir An increased rate of adverse events has been observed. Appropriate doses of the combinations with respect to safety and efficacy have not been established. HIV protease inhibitor: Saquinavir Fosamprenavir: ↓ Amprenavir Effect on saquinavir is not well established. Fosamprenavir/ ritonavir: Interaction has not been evaluated. Appropriate doses of the combination with respect to safety and efficacy have not been established. HIV integrase inhibitor: Raltegravir Fosamprenavir: ↓ Amprenavir ↓ Raltegravir Fosamprenavir/ ritonavir: ↓ Amprenavir ↓ Raltegravir Appropriate doses of the combination with respect to safety and efficacy have not been established. HIV integrase inhibitor: Dolutegravir Fosamprenavir/ ritonavir: ↓ Dolutegravir The recommended dose of dolutegravir is 50 mg twice daily when coadministered with fosamprenavir/ritonavir. Use an alternative combination where possible in patients with known or suspected integrase inhibitor resistance. HIV CCR5 co-receptor antagonist: Maraviroc Fosamprenavir/ ritonavir: ↓ Amprenavir ↑ Maraviroc No dosage adjustment required for fosamprenavir/ritonavir. The recommended dose of maraviroc is 150 mg twice daily when coadministered with fosamprenavir/ritonavir. Fosamprenavir should be given with ritonavir when coadministered with maraviroc.

Other Agents Alpha

1-adrenoreceptor antagonist: Alfuzosin ↑ Alfuzosin Coadministration is contraindicated due to potential hypotension [see Contraindications (4) ] . Antacid: MAALOX TC ® ↓ Amprenavir Use with caution when administered at the same time. Fosamprenavir may be less effective due to decreased amprenavir plasma concentrations. Staggered coadministration of antacids and fosamprenavir has not been evaluated. Antiarrhythmics: Amiodarone, disopyramide, lidocaine (systemic), and quinidine ↑ Antiarrhythmics Therapeutic concentration monitoring, if available, is recommended for antiarrhythmics. Antiarrhythmics: Flecainide, propafenone ↑ Antiarrhythmics Coadministration is contraindicated due to potential for serious and/or life-threatening reactions such as cardiac arrhythmias if fosamprenavir is co-prescribed with ritonavir [see Contraindications (4) ] . Anticoagulant: Warfarin Concentrations of warfarin may be affected. It is recommended that INR (international normalized ratio) be monitored. Anticonvulsants: Carbamazepine, phenobarbital, phenytoin Fosamprenavir: ↓ Amprenavir Use with caution. Fosamprenavir may be less effective due to decreased amprenavir plasma concentrations in patients taking these agents concomitantly.

Phenytoin

Fosamprenavir/ ritonavir: ↑ Amprenavir ↓ Phenytoin Plasma phenytoin concentrations should be monitored and phenytoin dose should be increased as appropriate. No change in fosamprenavir/ritonavir dose is recommended. Antidepressant: Paroxetine, trazodone ↓ Paroxetine Any paroxetine dose adjustment should be guided by clinical effect (tolerability and efficacy). ↑ Trazodone Adverse events of nausea, dizziness, hypotension, and syncope have been observed following coadministration of trazodone and ritonavir. If trazodone is used with a CYP3A4 inhibitor such as fosamprenavir, the combination should be used with caution and a lower dose of trazodone should be considered. Antifungals: Ketoconazole , itraconazole ↑ Ketoconazole ↑ Itraconazole Increase monitoring for adverse events. Fosamprenavir: Dose reduction of ketoconazole or itraconazole may be needed for patients receiving more than 400 mg ketoconazole or itraconazole per day. Fosamprenavir/ritonavir: High doses of ketoconazole or itraconazole (greater than 200 mg/day) are not recommended. Anti-gout: Colchicine ↑ Colchicine Patients with renal or hepatic impairment should not be given colchicine with fosamprenavir/ritonavir. Fosamprenavir/ritonavir and coadministration of colchicine: Treatment of gout flares: 0.6 mg (1 tablet) x 1 dose, followed by 0.3 mg (half tablet) 1 hour later. Dose to be repeated no earlier than 3 days. Prophylaxis of gout flares: If the original regimen was 0.6 mg twice a day, the regimen should be adjusted to 0.3 mg once a day. If the original regimen was 0.6 mg once a day, the regimen should be adjusted to 0.3 mg once every other day. Treatment of familial Mediterranean fever (FMF): Maximum daily dose of 0.6 mg (may be given as 0.3 mg twice a day). Fosamprenavir and coadministration of colchicine: Treatment of gout flares: 1.2 mg (2 tablets) x 1 dose. Dose to be repeated no earlier than 3 days. Prophylaxis of gout flares: If the original regimen was 0.6 mg twice a day, the regimen should be adjusted to 0.3 mg twice a day or 0.6 mg once a day. If the original regimen was 0.6 mg once a day, the regimen should be adjusted to 0.3 mg once a day. Treatment of FMF: Maximum daily dose of 1.2 mg (may be given as 0.6 mg twice a day). Antimycobacterial: Rifabutin ↑ Rifabutin and rifabutin metabolite A complete blood count should be performed weekly and as clinically indicated to monitor for neutropenia. Fosamprenavir: A dosage reduction of rifabutin by at least half the recommended dose is required. Fosamprenavir/ritonavir: Dosage reduction of rifabutin by at least 75% of the usual dose of 300 mg/day is recommended (a maximum dose of 150 mg every other day or 3 times per week). Antimycobacterial: Rifampin a ↓ Amprenavir Coadministration is contraindicated as it may lead to loss of virologic response and possible resistance to fosamprenavir or to the class of protease inhibitors [see Contraindications (4)] . Antineoplastics: Dasatinib, nilotinib, ibrutinib, vinblastine, everolimus ↑ Antineoplastics Fosamprenavir or fosamprenavir/ritonavir may increase plasma concentrations of antineoplastics metabolized by CYP3A, potentially increasing the risk of adverse events typically associated with these medications. In case of coadministration, please refer to relevant prescribing information for these medications. Antipsychotics: Lurasidone ↑ Lurasidone Fosamprenavir: If coadministration is necessary, reduce the lurasidone dose. Refer to the lurasidone prescribing information for concomitant use with moderate CYP3A4 inhibitors. Fosamprenavir/ritonavir: Use of lurasidone is contraindicated due to potential for serious and/or life-threatening reactions [see Contraindications (4) ] . Pimozide ↑ Pimozide Coadministration is contraindicated due to potential for serious and/or life-threatening reactions such as cardiac arrhythmias [see Contraindications (4) ] . Quetiapine ↑ Quetiapine Fosamprenavir/ritonavir: Initiation of fosamprenavir with ritonavir in patients taking quetiapine: Consider alternative antiretroviral therapy to avoid increases in quetiapine drug exposures. If coadministration is necessary, reduce the quetiapine dose to 1/6 of the current dose and monitor for quetiapine-associated adverse reactions. Refer to the quetiapine prescribing information for recommendations on adverse reaction monitoring. Initiation of quetiapine in patients taking fosamprenavir with ritonavir: Refer to the quetiapine prescribing information for initial dosing and titration of quetiapine. Benzodiazepines: Alprazolam, clorazepate, diazepam, flurazepam ↑ Benzodiazepines Clinical significance is unknown. A decrease in benzodiazepine dose may be needed. Calcium channel blockers: Diltiazem, felodipine, nifedipine, nicardipine, nimodipine, verapamil, amlodipine, nisoldipine, isradipine ↑ Calcium channel blockers Use with caution. Clinical monitoring of patients is recommended. Corticosteroid: Dexamethasone ↓ Amprenavir Use with caution. Fosamprenavir may be less effective due to decreased amprenavir plasma concentrations. Endothelin-receptor antagonist: Bosentan ↑ Bosentan Coadministration of bosentan in patients on fosamprenavir: In patients who have been receiving fosamprenavir for at least 10 days, start bosentan at 62.5 mg once daily or every other day based upon individual tolerability. Coadministration of fosamprenavir in patients on bosentan: Discontinue use of bosentan at least 36 hours prior to initiation of fosamprenavir. After at least 10 days following the initiation of fosamprenavir, resume bosentan at 62.5 mg once daily or every other day based upon individual tolerability. Ergot derivatives: Dihydroergotamine, ergonovine, ergotamine, methylergonovine ↑ Ergot derivatives Coadministration is contraindicated due to potential for serious and/or life-threatening reactions such as acute ergot toxicity characterized by peripheral vasospasm and ischemia of the extremities and other tissues [see Contraindications (4) ] . GI motility agent: Cisapride ↑ Cisapride Coadministration is contraindicated due to potential for serious and/or life-threatening reactions such as cardiac arrhythmias [see Contraindications (4) ] . Herbal product: St. John’s wort ( Hypericum perforatum ) ↓ Amprenavir Coadministration is contraindicated as it may lead to loss of virologic response and possible resistance to fosamprenavir or to the class of protease inhibitors [see Contraindications (4) ] . Histamine H 2 -receptor antagonists: Cimetidine, famotidine, nizatidine, ranitidine Fosamprenavir: ↓ Amprenavir Fosamprenavir/ ritonavir: Interaction not evaluated Use with caution. Fosamprenavir may be less effective due to decreased amprenavir plasma concentrations. Immunosuppressants: Cyclosporine, tacrolimus, sirolimus ↑ Immunosuppressants Therapeutic concentration monitoring is recommended for immunosuppressant agents. Inhaled beta-agonist: Salmeterol ↑ Salmeterol Concurrent administration of salmeterol with fosamprenavir is not recommended. The combination may result in increased risk of cardiovascular adverse events associated with salmeterol, including QT prolongation, palpitations, and sinus tachycardia. Inhaled/nasal steroid: Fluticasone Fosamprenavir: ↑ Fluticasone Fosamprenavir/ ritonavir: ↑ Fluticasone Use with caution. Consider alternatives to fluticasone, particularly for long-term use. May result in significantly reduced serum cortisol concentrations. Systemic corticosteroid effects including Cushing’s syndrome and adrenal suppression have been reported during postmarketing use in patients receiving ritonavir and inhaled or intranasally administered fluticasone. Coadministration of fluticasone and fosamprenavir/ritonavir is not recommended unless the potential benefit to the patient outweighs the risk of systemic corticosteroid side effects.

Lipid Modifying

Agents: HMG-CoA reductase inhibitors: Atorvastatin a ↑ Atorvastatin Titrate atorvastatin dose carefully and use the lowest necessary dose; do not exceed atorvastatin 20 mg/day. Lovastatin, simvastatin ↑ Lovastatin ↑ Simvastatin Coadministration with lovastatin or simvastatin is contraindicated due to potential for serious reactions such as risk of myopathy including rhabdomyolysis [see Contraindications (4) ] . Other lipid modifying agents: Lomitapide ↑ Lomitapide Coadministration with lomitapide is contraindicated due to potential for markedly increased transaminases. Narcotic analgesic: Methadone ↓ Methadone Data suggest that the interaction is not clinically relevant; however, patients should be monitored for opiate withdrawal symptoms. Fentanyl ↑ Fentanyl Careful monitoring of therapeutic effects and adverse effects of fentanyl (including potentially fatal respiratory depression) is recommended. Oral contraceptives: Ethinyl estradiol/norethindrone Fosamprenavir: ↓ Amprenavir ↓ Ethinyl estradiol Alternative methods of non-hormonal contraception are recommended. May lead to loss of virologic response. Fosamprenavir/ ritonavir: ↓ Ethinyl estradiol Increased risk of transaminase elevations. No data are available on the use of fosamprenavir/ritonavir with other hormonal therapies, such as hormone replacement therapy (HRT) for postmenopausal women. PDE5 inhibitors: Sildenafil, tadalafil, vardenafil ↑ Sildenafil ↑ Tadalafil ↑ Vardenafil May result in an increase in PDE5 inhibitor-associated adverse events, including hypotension, syncope, visual disturbances, and priapism. Use of PDE5 inhibitors for pulmonary arterial hypertension (PAH): Use of sildenafil (REVATIO) is contraindicated when used for the treatment of PAH. A safe and effective dose has not been established when used with fosamprenavir. There is increased potential for sildenafil-associated adverse events (which include visual disturbances, hypotension, prolonged erection, and syncope) [see Contraindications (4) ] .

• The following dose adjustments are recommended for use of tadalafil (ADCIRCA ® ) with fosamprenavir: Coadministration of ADCIRCA in patients on fosamprenavir: In patients receiving fosamprenavir for at least one week, start ADCIRCA at 20 mg once daily. Increase to 40 mg once daily based upon individual tolerability. Coadministration of fosamprenavir in patients on ADCIRCA: Avoid use of ADCIRCA during the initiation of fosamprenavir. Stop ADCIRCA at least 24 hours prior to starting fosamprenavir. After at least one week following the initiation of fosamprenavir, resume ADCIRCA at 20 mg once daily. Increase to 40 mg once daily based upon individual tolerability. Use of PDE5 inhibitors for erectile dysfunction: Fosamprenavir: Sildenafil: 25 mg every 48 hours. Tadalafil: no more than 10 mg every 72 hours. Vardenafil: no more than 2.5 mg every 24 hours. Fosamprenavir/ritonavir: Sildenafil: 25 mg every 48 hours. Tadalafil: no more than 10 mg every 72 hours. Vardenafil: no more than 2.5 mg every 72 hours. Use with increased monitoring for adverse events. Proton pump inhibitors: Esomeprazole , lansoprazole, omeprazole, pantoprazole, rabeprazole Fosamprenavir: ↔ Amprenavir ↑ Esomeprazole Fosamprenavir/ ritonavir: ↔ Amprenavir ↔ Esomeprazole Proton pump inhibitors can be administered at the same time as a dose of fosamprenavir with no change in plasma amprenavir concentrations. Sedative/hypnotics: Midazolam, triazolam ↑ Midazolam ↑ Triazolam Coadministration is contraindicated due to potential for serious and/or life-threatening reactions such as prolonged or increased sedation or respiratory depression [see Contraindications (4) ] . Tricyclic antidepressants: Amitriptyline, imipramine ↑ Tricyclics Therapeutic concentration monitoring is recommended for tricyclic antidepressants.

Drug Interaction

Studies [See Contraindications (4) , Warnings and Precautions (5.1) , Drug Interactions (7) .] Amprenavir, the active metabolite of fosamprenavir, is metabolized in the liver by the cytochrome P450 enzyme system. Amprenavir inhibits CYP3A4. Data also suggest that amprenavir induces CYP3A4. Caution should be used when coadministering medications that are substrates, inhibitors, or inducers of CYP3A4, or potentially toxic medications that are metabolized by CYP3A4. Amprenavir does not inhibit CYP2D6, CYP1A2, CYP2C9, CYP2C19, CYP2E1, or uridine glucuronosyltransferase (UDPGT). Amprenavir is both a substrate for and inducer of P-glycoprotein. Drug interaction trials were performed with fosamprenavir and other drugs likely to be coadministered or drugs commonly used as probes for pharmacokinetic interactions. The effects of coadministration on AUC, C max , and C min values are summarized in Table 10 (effect of other drugs on amprenavir) and Table 12 (effect of fosamprenavir on other drugs). In addition, since fosamprenavir delivers comparable amprenavir plasma concentrations as AGENERASE, drug interaction data derived from trials with AGENERASE are provided in Tables 11 and 13. For information regarding clinical recommendations, [see Drug Interactions (7) ] .

Table

10.

Drug

Interactions: Pharmacokinetic Parameters for Amprenavir after Administration of Fosamprenavir in the Presence of the Coadministered Drug(s) ↑ = Increase; ↓ = Decrease; ↔ = No change (↑ or ↓ less than or equal to 10%), NA = Not applicable.

Coadministered

Drug(s) and Dose(s) Dose of Fosamprenavir Concomitant medication is also shown in this column where appropriate. n % Change in Amprenavir Pharmacokinetic Parameters (90% CI) C max AUC C min Antacid (MAALOX TC) 30-mL single dose 1,400-mg single dose 30 ↓35 (↓24 to ↓42) ↓18 (↓9 to ↓26) ↑14 (↓7 to ↑39)

Atazanavir

300 mg once daily for 10 days 700 mg twice daily plus ritonavir 100 mg twice daily for 10 days 22 ↔ ↔ ↔ Atorvastatin 10 mg once daily for 4 days 1,400 mg twice daily for 2 weeks 16 ↓18 (↓34 to ↑1) ↓27 (↓41 to ↓12) ↓12 (↓27 to ↓6)

Atorvastatin

10 mg once daily for 4 days 700 mg twice daily plus ritonavir 100 mg twice daily for 2 weeks 16 ↔ ↔ ↔ Efavirenz 600 mg once daily for 2 weeks 1,400 mg once daily plus ritonavir 200 mg once daily for 2 weeks 16 ↔ ↓13 (↓30 to ↑7) ↓36 (↓8 to ↓56)

Efavirenz

600 mg once daily plus additional ritonavir 100 mg once daily for 2 weeks 1,400 mg once daily plus ritonavir 200 mg once daily for 2 weeks 16 ↑18 (↑1 to ↑38) ↑11 (0 to ↑24) ↔ Efavirenz 600 mg once daily for 2 weeks 700 mg twice daily plus ritonavir 100 mg twice daily for 2 weeks 16 ↔ ↔ ↓17 (↓4 to ↓29)

Esomeprazole

20 mg once daily for 2 weeks 1,400 mg twice daily for 2 weeks 25 ↔ ↔ ↔ Esomeprazole 20 mg once daily for 2 weeks 700 mg twice daily plus ritonavir 100 mg twice daily for 2 weeks 23 ↔ ↔ ↔ Ethinyl estradiol/ norethindrone 0.035 mg/0.5 mg once daily for 21 days 700 mg twice daily plus ritonavir Ritonavir C max , AUC, and C min increased by 63%, 45%, and 13%, respectively, compared with historical control. 100 mg twice daily for 21 days 25 ↔ Compared with historical control. ↔ ↔ Ketoconazole Subjects were receiving fosamprenavir/ritonavir for 10 days prior to the 4-day treatment period with both ketoconazole and fosamprenavir/ritonavir. 200 mg once daily for 4 days 700 mg twice daily plus ritonavir 100 mg twice daily for 4 days 15 ↔ ↔ ↔ Lopinavir/ritonavir 533 mg/133 mg twice daily 1,400 mg twice daily for 2 weeks 18 ↓13 Compared with fosamprenavir 700 mg/ritonavir 100 mg twice daily for 2 weeks. ↓26 ↓42 Lopinavir/ritonavir 400 mg/100 mg twice daily for 2 weeks 700 mg twice daily plus ritonavir 100 mg twice daily for 2 weeks 18 ↓58 (↓42 to ↓70) ↓63 (↓51 to ↓72) ↓65 (↓54 to ↓73)

Maraviroc

300 mg twice daily for 10 days 700 mg twice daily plus ritonavir 100 mg twice daily for 20 days 14 ↓34 (↓25 to ↓41) ↓35 (↓29 to ↓41) ↓36 (↓27 to ↓43)

Maraviroc

300 mg once daily for 10 days 1,400 mg once daily plus ritonavir 100 mg once daily for 20 days 14 ↓29 (↓20 to ↓38) ↓30 (↓23 to ↓36) ↓15 (↓3 to ↓25)

Methadone

70 to 120 mg once daily for 2 weeks 700 mg twice daily plus ritonavir 100 mg twice daily for 2 weeks 19 ↔ ↔ ↔ Nevirapine 200 mg twice daily for 2 weeks Subjects were receiving nevirapine for at least 12 weeks prior to trial. 1,400 mg twice daily for 2 weeks 17 ↓25 (↓37 to ↓10) ↓33 (↓45 to ↓20) ↓35 (↓50 to ↓15)

Nevirapine

200 mg twice daily for 2 weeks 700 mg twice daily plus ritonavir 100 mg twice daily for 2 weeks 17 ↔ ↓11 (↓23 to ↑3) ↓19 (↓32 to ↓4)

Phenytoin

300 mg once daily for 10 days 700 mg twice daily plus ritonavir 100 mg twice daily for 10 days 13 ↔ ↑20 (↑8 to ↑34) ↑19 (↑6 to ↑33)

Raltegravir

400 mg twice daily for 14 days 1,400 mg twice daily for 14 days (fasted) 14 ↓27 (↓46 to ↔) ↓36 (↓53 to ↓13) ↓43 C last (C 12 h or C 24 h ). (↓59 to ↓21) 1,400 mg twice daily for 14 days Doses of fosamprenavir and raltegravir were given with food on pharmacokinetic sampling days and without regard to food all other days. 14 ↓15 (↓27 to ↓1) ↓17 (↓27 to ↓6) ↓32 (↓53 to ↓1) 700 mg twice daily plus ritonavir 100 mg twice daily for 14 days (fasted) 14 ↓14 (↓39 to ↑20) ↓17 (↓38 to ↑12) ↓20 (↓45 to ↑17) 700 mg twice daily plus ritonavir 100 mg twice daily for 14 days 12 ↓25 (↓42 to ↓2) ↓25 (↓44 to ↔) ↓33 (↓52 to ↓7)

Raltegravir

400 mg twice daily for 14 days 1,400 mg once daily plus ritonavir 100 mg once daily for 14 days (fasted) 13 ↓18 (↓34 to ↔) ↓24 (↓41 to ↔) ↓50 (↓64 to ↓31) 1,400 mg once daily plus ritonavir 100 mg once daily for 14 days 14 ↑27 (↓1 to ↑62) ↑13 (↓7 to ↑38) ↓17 (↓45 to ↑26)

Ranitidine

300-mg single dose (administered 1 hour before fosamprenavir) 1,400-mg single dose 30 ↓51 (↓43 to ↓58) ↓30 (↓22 to ↓37) ↔ (↓19 to ↑21)

Rifabutin

150 mg every other day for 2 weeks 700 mg twice daily plus ritonavir 100 mg twice daily for 2 weeks 15 ↑36 (↑18 to ↑55) ↑35 (↑17 to ↑56) ↑17 (↓1 to ↑39)

Tenofovir

300 mg once daily for 4 to 48 weeks 700 mg twice daily plus ritonavir 100 mg twice daily for 4 to 48 weeks 45 NA NA ↔ Compared with parallel control group.

Tenofovir

300 mg once daily for 4 to 48 weeks 1,400 mg once daily plus ritonavir 200 mg once daily for 4 to 48 weeks 60 NA NA ↔ Table 11.

Drug

Interactions: Pharmacokinetic Parameters for Amprenavir after Administration of AGENERASE in the Presence of the Coadministered Drug(s) ↑ = Increase; ↓ = Decrease; ↔ = No change (↑ or ↓ less than 10%); NA = C min not calculated for single-dose trial.

Coadministered

Drug(s) and Dose(s) Dose of AGENERASE Compared with parallel control group. n % Change in Amprenavir Pharmacokinetic Parameters (90% CI) C max AUC C min Abacavir 300 mg twice daily for 2 to 3 weeks 900 mg twice daily for 2 to 3 weeks 4 ↔ ↔ ↔ Clarithromycin 500 mg twice daily for 4 days 1,200 mg twice daily for 4 days 12 ↑15 (↑1 to ↑31) ↑18 (↑8 to ↑29) ↑39 (↑31 to ↑47)

Delavirdine

600 mg twice daily for 10 days 600 mg twice daily for 10 days 9 ↑40 Median percent change; confidence interval not reported. ↑130 ↑125 Ethinyl estradiol/ norethindrone 0.035 mg/1 mg for 1 cycle 1,200 mg twice daily for 28 days 10 ↔ ↓22 (↓35 to ↓8) ↓20 (↓41 to ↑8)

Indinavir

800 mg 3 times a day for 2 weeks (fasted) 750 or 800 mg 3 times a day for 2 weeks (fasted) 9 ↑18 (↑13 to ↑58) ↑33 (↑2 to ↑73) ↑25 (↓27 to ↑116)

Ketoconazole

400-mg single dose 1,200-mg single dose 12 ↓16 (↓25 to ↓6) ↑31 (↑20 to ↑42) NA Lamivudine 150-mg single dose 600-mg single dose 11 ↔ ↔ NA Methadone 44 to 100 mg once daily for > 30 days 1,200 mg twice daily for 10 days 16 ↓27 Compared with historical data. ↓30 ↓25 Nelfinavir 750 mg 3 times a day for 2 weeks (fed) 750 or 800 mg 3 times a day for 2 weeks (fed) 6 ↓14 (↓38 to ↑20) ↔ ↑189 (↑52 to ↑448)

Rifabutin

300 mg once daily for 10 days 1,200 mg twice daily for 10 days 5 ↔ ↓15 (↓28 to 0) ↓15 (↓38 to ↑17)

Rifampin

300 mg once daily for 4 days 1,200 mg twice daily for 4 days 11 ↓70 (↓76 to ↓62) ↓82 (↓84 to ↓78) ↓92 (↓95 to ↓89)

Saquinavir

800 mg 3 times a day for 2 weeks (fed) 750 or 800 mg 3 times a day for 2 weeks (fed) 7 ↓37 (↓54 to ↓14) ↓32 (↓49 to ↓9) ↓14 (↓52 to ↑54)

Zidovudine

300-mg single dose 600-mg single dose 12 ↔ ↑13 (↓2 to ↑31) NA Table 12.

Drug

Interactions: Pharmacokinetic Parameters for Coadministered Drug in the Presence of Amprenavir after Administration of Fosamprenavir ↑ = Increase; ↓ = Decrease; ↔ = No change (↑ or ↓less than 10%); ND = Interaction cannot be determined as C min was below the lower limit of quantitation.

Coadministered

Drug(s) and Dose(s) Dose of Fosamprenavir Concomitant medication is also shown in this column where appropriate. n % Change in Pharmacokinetic Parameters of Coadministered Drug (90% CI) C max AUC C min Atazanavir 300 mg once daily for 10 days Comparison arm of atazanavir 300 mg once daily plus ritonavir 100 mg once daily for 10 days. 700 mg twice daily plus ritonavir 100 mg twice daily for 10 days 21 ↓24 (↓39 to ↓6) ↓22 (↓34 to ↓9) ↔ Atorvastatin 10 mg once daily for 4 days 1,400 mg twice daily for 2 weeks 16 ↑304 (↑205 to ↑437) ↑130 (↑100 to ↑164) ↓10 (↓27 to ↑12)

Atorvastatin

10 mg once daily for 4 days 700 mg twice daily plus ritonavir 100 mg twice daily for 2 weeks 16 ↑184 (↑126 to ↑257) ↑153 (↑115 to ↑199) ↑73 (↑45 to ↑108)

Esomeprazole

20 mg once daily for 2 weeks 1,400 mg twice daily for 2 weeks 25 ↔ ↑55 (↑39 to ↑73) ND Esomeprazole 20 mg once daily for 2 weeks 700 mg twice daily plus ritonavir 100 mg twice daily for 2 weeks 23 ↔ ↔ ND Ethinyl estradiol Administered as a combination oral contraceptive tablet: ethinyl estradiol 0.035 mg/norethindrone 0.5 mg. 0.035 mg once daily for 21 days 700 mg twice daily plus ritonavir 100 mg twice daily for 21 days 25 ↓28 (↓21 to ↓35) ↓37 (↓30 to ↓42) ND Dolutegravir 50 mg once daily 700 mg twice daily plus ritonavir 100 mg twice daily 12 ↓24 (↓8 to ↓37) ↓35 (↓22 to ↓46) ↓49 (↓37 to ↓59)

Ketoconazole

Subjects were receiving fosamprenavir/ritonavir for 10 days prior to the 4-day treatment period with both ketoconazole and fosamprenavir/ritonavir. 200 mg once daily for 4 days 700 mg twice daily plus ritonavir 100 mg twice daily for 4 days 15 ↑25 (↑0 to ↑56) ↑169 (↑108 to ↑248) ND Lopinavir/ritonavir Data represent lopinavir concentrations. 533 mg/133 mg twice daily for 2 weeks 1,400 mg twice daily for 2 weeks 18 ↔ Compared with lopinavir 400 mg/ritonavir 100 mg twice daily for 2 weeks. ↔ ↔ Lopinavir/ritonavir 400 mg/100 mg twice daily for 2 weeks 700 mg twice daily plus ritonavir 100 mg twice daily for 2 weeks 18 ↑30 (↓15 to ↑47) ↑37 (↓20 to ↑55) ↑52 (↓28 to ↑82)

Maraviroc

300 mg twice daily for 10 days 700 mg twice daily plus ritonavir 100 mg twice daily for 20 days 14 ↑52 (↑27 to ↑82) ↑149 (↑119 to ↑182) ↑374 (↑303 to ↑457)

Maraviroc

300 mg once daily for 10 days 1,400 mg once daily plus ritonavir 100 mg once daily for 20 days 14 ↑45 (↑20 to ↑74) ↑126 (↑99 to ↑158) ↑80 (↑53 to ↑113)

Methadone

70 to 120 mg once daily for 2 weeks 700 mg twice daily plus ritonavir 100 mg twice daily for 2 weeks 19 R-Methadone (active) ↓21 Dose normalized to methadone 100 mg. The unbound concentration of the active moiety, R-methadone, was unchanged. (↓30 to ↓12) ↓18 (↓27 to ↓8) ↓11 (↓21 to ↑1) S-Methadone (inactive) ↓43 (↓49 to ↓37) ↓43 (↓50 to ↓36) ↓41 (↓49 to ↓31)

Nevirapine

200 mg twice daily for 2 weeks Subjects were receiving nevirapine for at least 12 weeks prior to trial. 1,400 mg twice daily for 2 weeks 17 ↑25 (↑14 to ↑37) ↑29 (↑19 to ↑40) ↑34 (↑20 to ↑49)

Nevirapine

200 mg twice daily for 2 weeks 700 mg twice daily plus ritonavir 100 mg twice daily for 2 weeks 17 ↑13 (↑3 to ↑24) ↑14 (↑5 to ↑24) ↑22 (↑9 to ↑35)

Norethindrone

0.5 mg once daily for 21 days 700 mg twice daily plus ritonavir 100 mg twice daily for 21 days 25 ↓38 (↓32 to ↓44) ↓34 (↓30 to ↓37) ↓26 (↓20 to ↓32)

Phenytoin

300 mg once daily for 10 days 700 mg twice daily plus ritonavir 100 mg twice daily for 10 days 14 ↓20 (↓12 to ↓27) ↓22 (↓17 to ↓27) ↓29 (↓23 to ↓34)

Rifabutin

150 mg every other day for 2 weeks Comparison arm of rifabutin 300 mg once daily for 2 weeks. AUC is AUC (0-48 h) . 700 mg twice daily plus ritonavir 100 mg twice daily for 2 weeks 15 ↓14 (↓28 to ↑4) ↔ ↑28 (↑12 to ↑46) (25-O-desacetylrifabutin metabolite) ↑579 (↑479 to ↑698) ↑1,120 (↑965 to ↑1,300) ↑2,510 (↑1,910 to ↑3,300) Rifabutin + 25-O-desacetylrifabutin metabolite NA ↑64 (↑46 to ↑84) NA Rosuvastatin 10-mg single dose 700 mg twice daily plus ritonavir 100 mg twice daily for 7 days ↑45 ↑8 NA Table 13.

Drug

Interactions: Pharmacokinetic Parameters for Coadministered Drug in the Presence of Amprenavir after Administration of AGENERASE ↑ = Increase; ↓ = Decrease; ↔ = No change (↑ or ↓ less than 10%); NA = C min not calculated for single-dose trial; ND = Interaction cannot be determined as C min was below the lower limit of quantitation.

Coadministered

Drug(s) and Dose(s) Dose of AGENERASE n % Change in Pharmacokinetic Parameters of Coadministered Drug (90% CI) C max AUC C min Abacavir 300 mg twice daily for 2 to 3 weeks 900 mg twice daily for 2 to 3 weeks 4 ↔ Compared with historical data. ↔ ↔ Clarithromycin 500 mg twice daily for 4 days 1,200 mg twice daily for 4 days 12 ↓10 (↓24 to ↑7) ↔ ↔ Delavirdine 600 mg twice daily for 10 days 600 mg twice daily for 10 days 9 ↓47 Median percent change; confidence interval not reported. ↓61 ↓88 Ethinyl estradiol 0.035 mg for 1 cycle 1,200 mg twice daily for 28 days 10 ↔ ↔ ↑32 (↓3 to ↑79)

Indinavir

800 mg 3 times a day for 2 weeks (fasted) 750 mg or 800 mg 3 times a day for 2 weeks (fasted) 9 ↓22 ↓38 ↓27 Ketoconazole 400-mg single dose 1,200-mg single dose 12 ↑19 (↑8 to ↑33) ↑44 (↑31 to ↑59) NA Lamivudine 150-mg single dose 600-mg single dose 11 ↔ ↔ NA Methadone 44 mg to 100 mg once daily for > 30 days 1,200 mg twice daily for 10 days 16 R-Methadone (active) ↓25 (↓32 to ↓18) ↓13 (↓21 to ↓5) ↓21 (↓32 to ↓9) S-Methadone (inactive) ↓48 (↓55 to ↓40) ↓40 (↓46 to ↓32) ↓53 (↓60 to ↓43)

Nelfinavir

750 mg 3 times a day for 2 weeks (fed) 750 mg or 800 mg 3 times a day for 2 weeks (fed) 6 ↑12 ↑15 ↑14 Norethindrone 1 mg for 1 cycle 1,200 mg twice daily for 28 days 10 ↔ ↑18 (↑1 to ↑38) ↑45 (↑13 to ↑88)

Rifabutin

300 mg once daily for 10 days 1,200 mg twice daily for 10 days 5 ↑119 (↑82 to ↑164) ↑193 (↑156 to ↑235) ↑271 (↑171 to ↑409)

Rifampin

300 mg once daily for 4 days 1,200 mg twice daily for 4 days 11 ↔ ↔ ND Saquinavir 800 mg 3 times a day for 2 weeks (fed) 750 mg or 800 mg 3 times a day for 2 weeks (fed) 7 ↑21 ↓19 ↓48 Zidovudine 300-mg single dose 600-mg single dose 12 ↑40 (↑14 to ↑71) ↑31 (↑19 to ↑45) NA

4 CONTRAINDICATIONS

• Fosamprenavir calcium tablets are contraindicated in patients with previously demonstrated clinically significant hypersensitivity (e.g., Stevens-Johnson syndrome) to any of the components of this product or to amprenavir.
• Fosamprenavir calcium tablets are contraindicated when coadministered with drugs that are highly dependent on cytochrome P450 (CYP)3A4 for clearance and for which elevated plasma concentrations are associated with serious and/or life-threatening events. These drugs and other contraindicated drugs (which may lead to reduced efficacy of fosamprenavir and possible resistance) are listed below [see Drug Interactions (7), Clinical Pharmacology (12.3)]. The list of contraindicated drugs applies to the use of fosamprenavir with or without ritonavir, unless otherwise indicated. If fosamprenavir is coadministered with ritonavir, reference should be made to the full prescribing information for ritonavir for additional contraindications.
• Fosamprenivir is contraindicated when coadministered with the following drugs: o Alpha 1-adrenoreceptor antagonist: Alfuzosin o Antiarrhythmics: Flecainide (with ritonavir ), propafenone (with ritonavir ) o Antimycobacterial: Rifampin o Antipsychotic: Lurasidone (with ritonavir ), pimozide o Ergot derivatives: Dihydroergotamine, ergonovine, ergotamine, methylergonovine o GI motility agent: Cisapride o Herbal product: St. John’s wort ( Hypericum perforatum ) o Lipid modifying agents: Lomitapide, lovastatin, simvastatin o Non-nucleoside reverse transcriptase inhibitor: Delavirdine o PDE5 inhibitor: Sildenafil (REVATIO ® ) (for treatment of pulmonary arterial hypertension) o Sedative/hypnotics: Midazolam, triazolam
• Hypersensitivity to fosamprenavir or amprenavir (e.g., Stevens-Johnson syndrome). ( 4 )
• Drugs highly dependent on cytochrome P450 (CYP)3A4 for clearance and for which elevated plasma levels may result in serious and/or life-threatening events. ( 4 )
• Review ritonavir contraindications when used in combination. ( 4 )

AND PRECAUTIONS The concomitant use of fosamprenavir calcium with ritonavir and certain other drugs may result in known or potentially significant drug interactions. Consult the full prescribing information prior to and during treatment for potential drug interactions. (5.1, 7.3) Fosamprenavir calcium should be discontinued for severe skin reactions, including Stevens-Johnson syndrome. (5.2) Fosamprenavir calcium should be used with caution in patients with a known sulfonamide allergy. (5.3) Use of higher-than-approved doses may lead to transaminase elevations. Patients with hepatitis B or C are at increased risk of transaminase elevations. (5.4) Patients receiving fosamprenavir calcium may develop new onset or exacerbations of diabetes mellitus, hyperglycemia (5.5), immune reconstitution syndrome (5.6), increase of body fat (5.7), and elevated triglyceride and cholesterol concentrations (5.8). Monitor cholesterol and triglycerides prior to therapy and periodically thereafter. Acute hemolytic anemia has been reported with amprenavir. (5.9) Hemophilia: Spontaneous bleeding may occur, and additional factor VIII may be required. (5.10) Nephrolithiasis: Cases of nephrolithiasis have been reported with fosamprenavir. (5.11)

5.1 Risk of Serious Adverse Reactions Due to Drug Interactions Initiation of fosamprenavir calcium/ritonavir, a CYP3A inhibitor, in patients receiving medications metabolized by CYP3A, or initiation of medications metabolized by CYP3A in patients already receiving fosamprenavir calcium/ritonavir may increase plasma concentrations of medications metabolized by CYP3A. Initiation of medications that inhibit or induce CYP3A may increase or decrease concentrations of fosamprenavir calcium/ritonavir, respectively. These interactions may lead to: clinically significant adverse reactions, potentially leading to severe, life-threatening, or fatal events from greater exposures of concomitant medications. clinically significant adverse reactions from greater exposures of fosamprenavir calcium/ritonavir. loss of therapeutic effect of fosamprenavir calcium/ritonavir and possible development of resistance.

See Table

6 for steps to prevent or manage these possible and known significant drug interactions, including dosing recommendations [see Drug Interactions (7)] . Consider the potential for drug interactions prior to and during therapy with fosamprenavir calcium/ritonavir; review concomitant medications during therapy with fosamprenavir calcium/ritonavir, and monitor for the adverse reactions associated with the concomitant medications [see Contraindications (4), Drug Interactions (7)] .

5.2 Skin Reactions Severe and life-threatening skin reactions, including 1 case of Stevens-Johnson syndrome among 700 subjects treated with fosamprenavir calcium in clinical trials. Treatment with fosamprenavir calcium should be discontinued for severe or life-threatening rashes and for moderate rashes accompanied by systemic symptoms <span class="opacity-50 text-xs">[see Adverse Reactions (6)]</span> .

5.3 Sulfa Allergy Fosamprenavir calcium should be used with caution in patients with a known sulfonamide allergy. Fosamprenavir contains a sulfonamide moiety. The potential for cross-sensitivity between drugs in the sulfonamide class and fosamprenavir is unknown. In a clinical trial of fosamprenavir calcium used as the sole protease inhibitor, rash occurred in 2 of 10 subjects (20%) with a history of sulfonamide allergy compared with 42 of 126 subjects (33%) with no history of sulfonamide allergy.

In

2 clinical trials of fosamprenavir calcium plus low-dose ritonavir, rash occurred in 8 of 50 subjects (16%) with a history of sulfonamide allergy compared with 50 of 412 subjects (12%) with no history of sulfonamide allergy.

5.4 Hepatic Toxicity Use of fosamprenavir calcium with ritonavir at higher-than-recommended dosages may result in transaminase elevations and should not be used <span class="opacity-50 text-xs">[see Dosage and Administration (2), Overdosage (10)]</span> . Patients with underlying hepatitis B or C or marked elevations in transaminases prior to treatment may be at increased risk for developing or worsening of transaminase elevations. Appropriate laboratory testing should be conducted prior to initiating therapy with fosamprenavir calcium and patients should be monitored closely during treatment.

5.5 Diabetes/Hyperglycemia New onset diabetes mellitus, exacerbation of pre-existing diabetes mellitus, and hyperglycemia have been reported during postmarketing surveillance in HIV-1-infected patients receiving protease inhibitor therapy. Some patients required either initiation or dose adjustments of insulin or oral hypoglycemic agents for treatment of these events. In some cases, diabetic ketoacidosis has occurred. In those patients who discontinued protease inhibitor therapy, hyperglycemia persisted in some cases. Because these events have been reported voluntarily during clinical practice, estimates of frequency cannot be made and causal relationships between protease inhibitor therapy and these events have not been established.

5.6 Immune Reconstitution Syndrome Immune reconstitution syndrome has been reported in patients treated with combination antiretroviral therapy, including fosamprenavir calcium. During the initial phase of combination antiretroviral treatment, patients whose immune systems respond may develop an inflammatory response to indolent or residual opportunistic infections (such as Mycobacterium avium infection, cytomegalovirus, Pneumocystis jirovecii pneumonia [PCP], or tuberculosis), which may necessitate further evaluation and treatment. Autoimmune disorders (such as Graves’ disease, polymyositis, and Guillain-Barré syndrome) have also been reported to occur in the setting of immune reconstitution; however, the time to onset is more variable, and can occur many months after initiation of treatment.

5.7 Increase in Body Fat Increase of body fat has been observed in patients receiving protease inhibitors, including fosamprenavir calcium. The mechanism and long-term consequences of these events are currently unknown. A causal relationship has not been established.

5.8 Lipid Elevations Treatment with fosamprenavir calcium plus ritonavir has resulted in increases in the concentration of triglycerides and cholesterol <span class="opacity-50 text-xs">[see Adverse Reactions (6)]</span> . Triglyceride and cholesterol testing should be performed prior to initiating therapy with fosamprenavir calcium and at periodic intervals during therapy. Lipid disorders should be managed as clinically appropriate <span class="opacity-50 text-xs">[see Drug Interactions (7)]</span> .

5.9 Hemolytic Anemia Acute hemolytic anemia has been reported in a patient treated with amprenavir.

5.10 Patients with Hemophilia There have been reports of spontaneous bleeding in patients with hemophilia A and B treated with protease inhibitors. In some patients, additional factor VIII was required. In many of the reported cases, treatment with protease inhibitors was continued or restarted. A causal relationship between protease inhibitor therapy and these episodes has not been established.

5.11 Nephrolithiasis Cases of nephrolithiasis were reported during postmarketing surveillance in HIV-1-infected patients receiving fosamprenavir calcium. Because these events were reported voluntarily during clinical practice, estimates of frequency cannot be made. If signs or symptoms of nephrolithiasis occur, temporary interruption or discontinuation of therapy may be considered.

5.12 Resistance/Cross-Resistance Because the potential for HIV cross-resistance among protease inhibitors has not been fully explored, it is unknown what effect therapy with fosamprenavir calcium will have on the activity of subsequently administered protease inhibitors. Fosamprenavir calcium has been studied in patients who have experienced treatment failure with protease inhibitors <span class="opacity-50 text-xs">[see Clinical Studies (14.2)]</span> .